This proposal includes trade secrets and other proprietary or confidential information of Highland Instruments and is being provided for use by the National Institutes of Health (NIH) for the sole purpose of evaluating this SBIR proposal. No other rights are conferred. This proposal and the trade secrets and other proprietary or confidential information contained herein shall further not be disclosed in whole or in parts, outside of NIH without Highland Instrument's permission. This restriction does not limit the NIH's right to use information contained in the data if it is obtained from another source without restriction. This legend applies to the entire proposal, including, but not limited to the Abstract Introduction, Specific Aims, Research Plan (all components), Commercialization Plan, and Human Subject's Sections of this proposal. Abstract. OA of the knee is a leading cause of chronic pain and disability [1]. Conventional treatments do not directly address the fact that pain sensation is processed in the brain [2-5] and mechanical joint dysfunction can be worsened by chronic pain induced changes in the brain's motor control centers [6]. Non-Invasive Brain Stimulation (NIBS) has been successfully applied for the treatment of chronic pain in some disease states, where treatment induced changes in brain activity revert maladaptive plasticity associated with the perception/sensation of chronic pain [3, 5, 7]. However the most common NIBS methods, Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), fail to show consistent clinical benefit on par with that of the conventional pain treatments and are not commonly used for OA therapy [8, 9]. It has been postulated that limitations in these techniques' focality, penetration, and targeting control limit their therapeutc efficacy [10-14]. Electrosonic Stimulation (ESStim(tm)) is an improved NIBS modality that overcomes the limitations of other technologies by combining independently controlled electromagnetic and ultrasonic fields to focus and boost stimulation currents via tuned electromechanical coupling in neural tissue. This proposal is focused on evaluating whether our noninvasive ESStim system can effectively treat chronic OA pain, and in turn improve knee biomechanical function and patient quality of life (QOL). First in Phase I to assess the feasibilit of the proposed work, we will follow 16 OA patients after giving a constant fixed dose of ESStim for 20 min/day on 5 consecutive days (8 SHAM ESStim, 8 ESStim). We will assess a battery of safety, pain, biomechanical knee function, and QOL measures in the patients, evaluated over the treatment period and for at least six weeks following the last treatment session. Next in Phase II, we will follow 64 OA patients after giving a constant fixed dose of stimulation for 10 days, 20 min/day, over a two-week period. Patients will randomly be assigned to 1 of 4 stimulation conditions: ESStim, tDCS, transcranial ultrasound (TUS), or SHAM ESStim. We will evaluate these patients with the battery of pain, biomechanical, QOL, and safety measures, which were validated in the Phase I studies, and compare the efficacy of the tested interventions for at least eight weeks following the last treatment session. Furthermore, we will test whether the ESStim pain suppression can be guided by the baseline disease state. To test this we will build and evaluate multivariate linear and generalized linear regression models to predict the clinical outcomes and identify best responders. Overall, we hypothesize that the proposed experiments, computational studies, and technology development will allow us to test the effectiveness of ESStim in OA patients. The work will serve as the basis for a future large-scale multicenter study and further the commercialization of ESStim OA therapy.